2-[8-quinolinyl]-sulphinyl-1H-benzimidazole

ABSTRACT

Novel compounds of the formula IIIa ##STR1## wherein R 1a , R 2a , R 3a  and R 4a  are the same or different and are hydrogen, an alkyl, alkoxy optionally completely or predominantly substituted by fluorine or chlorine, halogen, --CN, --CF 3 , --NO 2 , --COR, --COOR, aryl, aryloxy or arylalkoxy group, or adjacent groups R 1a , R 2a , R 3a  and R 4a  together with the adjacent carbon atoms in the benzimidazole ring form a 5-, 6- or 7-membered monocyclic ring or a 9-, 10- or 11-membered bicyclic ring, which rings may be saturated or unsaturated and may contain 0-3 heteroatoms selected from N and O and which rings may be optionally substituted with 1-4 substitutents selected from alkyl groups with 1-3 carbon atoms, halogen preferably F or Cl, alkylene radicals containing 4-5 carbon atoms giving spiro compounds, or two or four of these substituents together form one or two oxy groups ##STR2## whereby if R 1a , R 2a , R 3a  and R 4a  together with the adjacent carbon atoms in the benzimidazole ring form two rings they may be condensed with each other, R 5a  is hydrogen or an alkyl group, R 6a  is hydrogen or an alkyl group or R 5a  and R 6a  are joined together to form an alkylene chain, R 7a  is hydrogen, an alkyl, alkoxy, alkenyloxy or alkynyloxy group, R 8a  is hydrogen or an alkyl group, or R 6a  and R 7a , or R 7a  and R 8a  together with the adjacent carbon atoms in the pyridinium ring form a ring wherein the part constituted by R 6a  and R 7a  or R 7a  and R 8a , is --CH═CH--CH═CH--, --O--(CH 2 ) p  --, --CH 2  (CH 2 ) p  --, --O--CH═CH--, --NH--CH═CH--, ##STR3## or --S--(CH 2 ) p  --, wherein p is 2, 3 or 4 and the O, S and N atoms always are attached to position 3 in the compound IIIa, R is a alkyl, cycloalkyl, aryl or arylalkyl group, and X -  is a pharmaceutically acceptable anion, process for preparation thereof, pharmaceutical compositions containing such compounds and their use in medicine.

This application is a division of application Ser. No. 739,425, filed onMay 30, 1985 now U.S. Pat. No. 4,636,499 issued 1/13/87.

FIELD OF THE INVENTION

The present invention is related to new sulphenamide salts havingvaluable therapeutic properties especially in affecting gastric acidsecretion and providing gastrointestinal cytoprotective effect inmammals, including man, as well as processes for the preparation of thenew compounds, pharmaceutical compositions comprising them and a methodof affecting gastric acid secretion and providing gastrointestinalcytoprotective effect when using them.

BACKGROUND OF THE INVENTION

From e.g. EP-Al-0 005 129 sulphoxides of the benzimidazole type with thegeneral formula I ##STR4## in which R¹ and R² are the same or differentand are hydrogen, alkyl, halogen, methoxycarbonyl, ethoxycarbonyl,alkoxy, or alkanoyl in any position, R⁶ is hydrogen, methyl or ethyl,R³, R⁴ and R⁵ are the same or different and are each hydrogen, methyl,methoxy, ethoxy, methoxyethoxy or ethoxyethoxy, whereby R³, R⁴ and R⁵are not all hydrogen, and whereby when two of R³, R⁴ and R⁵ arehydrogen, the third of R³, R⁴ and R⁵ is not methyl, as well aspharmaceutically acceptable salts thereof are known. The compounds withthe general formula I can be used in the treatment of gastrointestinaldiseases.

The compounds are known to inhibit gastric acid secretion and have alsoa gastric cytoprotective effect. Because of their antisecretory effectthey may be used in the treatment of peptic ulcer.

The antisecretory activity of the substituted benzimidazoles with thegeneral formula I has been found to be mediated by inhibition of thegastric H⁺,K⁺ -ATPase, the enzyme responsible for the pumping of protonsinto the stomach. This enzyme is localized in the parietal cells in thegastric mucosa.

The in vivo inhibiting effect of the compounds with the general formulaI is not, however, exerted by the compounds as such but by one or moredegradation products.

OUTLINE OF THE INVENTION

According to the present invention it has now surprisingly been foundthat the above mentioned degradation reaction of the sulphoxides withthe general formula I is a complicated transformation reaction to thenew sulphenamides with the general formula III ##STR5## wherein R¹, R²,R³, R⁴, R⁵ and R⁶ have the same meaning as given above and X⁻ is apharmaceutically acceptable anion.

Compounds of the invention are compounds of the general formula IIIa##STR6## wherein R^(1a), R^(2a), R^(3a) and R^(4a) are the same ordifferent and are hydrogen an alkyl, alkoxy, optionally completely orpredominantly substituted by fluorine or chlorine, halogen, --CN, --CF₃,--NO₂, --COR, --COOR, aryl, aryloxy or arylalkoxy group, or adjacentgroups R^(1a), R^(2a), R^(3a) and R^(4a) together with the adjacentcarbon atoms in the benzimidazole ring form a 5-, 6- or 7-memberedmonocyclic ring or a 9-, 10- or 11-membered bicyclic ring, which ringsmay be saturated or unsaturated and may contain 0-3 hetero atomsselected from N and O and which rings may be optionally substituted with1-4 substituents selected from alkyl groups with 1-3 carbon atoms,halogen preferably F or Cl, alkylene radicals containing 4-5 carbonatoms giving spiro compounds, or two or four of these substituentstogether form one or two oxy groups ##STR7## whereby if R^(1a), R^(2a),R^(3a) and R^(4a) together with the adjacent carbon atoms in thebenzimidazole ring form two rings they may be condensed with each other,R^(5a) is hydrogen or an alkyl group, R^(6a) is hydrogen or an alkylgroup or R^(5a) and R^(6a) are joined together to form an alkenylenechain, R^(7a) is hydrogen, an alkyl, alkoxy, alkenyloxy or alkynyloxygroup, R^(8a) is hydrogen or an alkyl group, or R^(6a) and R^(7a), orR^(7a) and R^(8a) together with the adjacent carbon atoms in thepyridinium ring form a ring wherein the part constituted by R^(6a) andR^(7a) or R^(7a) and R^(8a), is --CH═CH--CH═CH--, --O--(CH₂)_(p) --,--CH₂ (CH₂)_(p) --O--CH═CH--, --NH--CH═CH--, ##STR8## or --S--(CH₂)_(p)--, wherein p is 2, 3 or 4 and the O, S and N atoms always are attachedto position 3 in the compound IIIa, R is an alkyl, cycloalkyl, aryl orarylalkyl group, and X⁻ is a pharmaceutically acceptable anion e.g. Cl⁻,Br⁻, I⁻, BF₄ ⁻, PF₆ ⁻ or AuCl₄ ⁻.

R^(1a), R^(2a), R^(3a), R^(4a), R^(5a), R^(6a), R^(7a), R^(8a) and Rrepresenting an alkyl group is preferably a lower alkyl group having 1-7carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl orisobutyl.

R^(1a), R^(2a), R^(3a), R^(4a) and R^(7a) representing an alkoxy groupis preferably a lower alkoxy group having 1-7 carbon atoms, expeciallypreferred 1-3 carbon atoms e.g. methoxy, ethoxy, n-propoxy orisopropoxy.

R^(1a), R^(2a), R^(3a) and R^(4a) representing a halogen is chloro,bromo, fluoro or iodo.

R^(1a), R^(2a), R^(3a), R^(4a) and R representing an aryl has preferablyup to 10 carbon atoms, especially preferred up to 6 carbon atoms e.g.phenyl.

R^(1a), R^(2a), R^(3a) and R^(4a) representing an aryloxy grop haspreferably up to 10 carbon atoms, especially preferred up to 6 carbonatoms, e.g. phenoxy.

R^(1a), R^(2a), R^(3a) and R^(4a) representing an arylalkoxy group and Rrepresenting an arylalkyl group, have preferably up to 10 carbon atomsin the aryl group and 1-7 carbon atoms in the alkoxy group or the alkylgroup, respectively, especially preferred is a group having up to 6carbon atoms in the aryl group and 1-3 carbon atoms in the alkoxy groupor the alkyl group, respectively, e.g. phenylmethoxy, and phenylmethyl.

R^(5a) and R^(6a) representing an alkenylene chain having 3 carbonatoms, thus forming a quinoline ring is especially preferred.

R^(7a) representing an alkenyloxy or alkynyloxy group has preferably 2-5carbon atoms, especially preferred 3 carbon atoms.

R representing a cycloalkyl group has preferably 3-10 carbon atoms,especially preferred 3 carbon atoms.

A preferred group of compounds with the general formula IIIa are thosewherein at least two of R^(1a), R^(2a), R^(3a) and R^(4a) are hydrogenand one or two of the other is a methyl group, R^(5a) is hydrogen, atleast one of R^(6a) and R^(8a) is a methyl group and R^(7a) is hydrogenor a methoxy group.

Especially preferred according to the invention is the isomeric mixtureof2,4-dimethyl-3,9-dimethoxy-5H-pyrido[1',2':4,5][1,2,4]thiadiazino[2,3-a]benzimidazol-13-iumtetrafluoroborate and2,4-dimethyl-3,10-dimethoxy-5H-pyrido[1',2':4,5][1,2,4]thiadiaziazino[2,3-a]benzimidazol-13-iumtetrafluoroborate.

The new compounds with the general formula IIIa according to thisinvention are potent enzyme inhibitors, primarily inhibitors of theenzyme H⁺,K⁺ -ATPase. In addition, the new compounds exhibit agastrointestinal cytoprotective effect. In the form of a suitablepharmaceutical composition, the new compounds are therapeuticallyuseful, primarily in the treatment of gastric disorders, such asgastrointestinal inflammatory diseases, including e.g. gastritis,gastric and duodenal ulcer. They may also be used as gastrointestinalcytoprotecting agents.

Compounds of the general formula IIIa above may be prepared according tothe following method ##STR9##

The transformation reaction probably goes via the sulphenic acid IIa,which may also be an in vivo inhibitor, when a sulphoxide with thegeneral formula Ia has been administered. However, the sulphenic acid isprobably not an isolable compound. The transformation from thesulphoxide to the sulphenamide goes via two different pathways, namely

(a) one acid catalyzed and

(b) one non-acid catalyzed pathway. Both pathways, however, give thesame sulphenamide, IIIa.

Especially preferred acids for preparation of the compounds with thegeneral formula IIIa are HPF₆, HBF₄, HAuCl₄ and HCl.

The compounds with the general formula Ia, wherein R^(5a) and R^(6a)together form an alkenylene chain are new compounds, which form a partof the invention.

The compounds with the general formula IIa are new compounds, which forma part of the invention.

Method (a)

0.005 mole of a sulphoxide with the general formula Ia is dissolved in50 ml of 0.2M HCl in CH₃ OH (1 ml of HCl and 49 ml of CH₃ OH) at 37° C.and is stirred for 7 minutes. (1 ml of acid HPF₆, HBF₄ or HAuCl₄) isadded and the solution is cooled to 10° C. Crystals of the sulphenamidewith the general formula IIIa are precipitated, filtered off and dried.

Method (b)

0.005 mole of a sulphoxide with the general formula Ia is dissolved in50 ml of 0.2M HCl in CH₃ OH (1 ml of HCl and 49 ml of CH₃ OH) at 37° C.and is stirred for 7 min. The solution is cooled, whereby a sulphenamidewith the general formula IIIa is precipitated as its Cl⁻ -salt. Theprecipitate is filtered off and dried.

Method (b)

0.01 mole of a sulphoxide with the general formula Ia is dissolved in100 ml 0.2M methanolic HBF₄ (2.5 ml 50% HBF₄ and 97.5 ml of CH₃ OH) at37° C. and is stirred for 2 min. 50 ml of MeOH is added and the mixtureis then stirred for another 3 min at 37° C. The mixture is cooled to 5°C. Crystals of the sulphenamide with the general formula IIIa areprecipitated, filtered off and dried.

The invention also relates to pharmaceutical compositions containing thenew sulphenamides as active ingredient; to the use of the novelsulphenamides in therapy, especially for providing gastrointestinalcytoprotective effects in mammals and man; to the use of the novelsulphenamides in the prevention and treatment of gastrointestinalinflammatory diseases in mammals and man; to a method for inhibitinggastric acid secretion in mammals and man by administering a compound ofthe formula IIIa, to a method for the treatment of gastrointestinalinflammatory diseases in mammals and man by administering a compound ofthe formula IIIa; and to a method for providing gastrointestinalcytoprotective effects mammals and man by administering a compound ofthe formula IIIa.

For clinical use the compounds of the invention are formulated intopharmaceutical formulations for oral, rectal, parenteral or other modeof administration. The pharmaceutical formulation contains a compound ofthe invention in combination with a pharmaceutically acceptable carrier.The carrier may be in the form of a solid, semisolid or liquid diluent,or a capsule. These pharmaceutical preparations are a further object ofthe invention. Usually the amount of active compound is between 0.1-95%by weight of the preparation.

In the preparation of pharmaceutical formulations containing a compoundof the present invention in the form of dosage units for oraladministration the compound selected may be mixed with a solid, powderedcarrier, e.g. calcium phosphate, lactose, saccharose, sorbitol,mannitol, starch, amylopectin, cellulose derivatives or gelatin, as wellas with lubricating agents e.g. magnesium stearate, calcium stearate,sodium steryl fumarate and polyethylene glycol waxes. The mixture isthen processed into granules or pressed into tablets. The tablets may befilm coated by a suitable film-forming material.

Soft gelatine capsules may be prepared with capsules containing amixture of the active compound or compounds of the invention and asuitable vehicle for soft gelatine capsules. Hard gelatine capsules mayalso contain the active compound in combination with a solid powderedcarrier e.g. lactose, saccharose, sorbitol, mannitol, potato starch,corn starch, amylopectin, cellulose derivatives or gelatine.

The oral dosage forms may be enteric coated. The enteric coating ischosen among pharmaceutically acceptable enteric-coating materials e.g.beeswax, shellac or anionic film-forming polymers such as celluloseacetate phthalate, hydroxypropyl methylcellulose phthalate, partlymethyl esterified methacrylic acid polymers and the like, if preferredin combination with a suitable plasticizer. To this coating various dyesmay be added in order to distinguish among tablets or granules withdifferent active compounds or with different amounts of the activecompound present.

The typical daily dose of the active substance varies within a widerange and will depend on various factors such as for example theindividual requirement of each patient, the manner of administration andthe disease. In general, oral and parenteral dosages will be in therange of 1 to 400 mg per day of active substance.

EXAMPLE 1A+1B2,4-Dimethyl-3,9-dimethoxy-5H-pyrido[1',2':4,5][1,2,4]thiadiazino[2,3-a]benzimidazol-13-iumtetrafluoroborate (1A) and2,4-Dimethyl-3,10-dimethoxy-5H-pyrido[1',2':4,5][1,2,4]thiadiazino[2,3-a]benzimidazol-13-iumtetrafluoroborate (1B) (isomeric mixture)

Method a

5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole(1.72 g, 0.005 mol) was dissolved in 0.2M methanolic HCl (50 ml) (1 mlconc. HCl and 49 ml CH₃ OH) and stirred at 37° C. for 7 min. Conc. HBF₄(1 ml) was added and the solution was cooled to 10° C. The desiredmixture of the isomeric sulphenamide products was filtered off as acrystalline material and dried. Yield: 1.25 g (60%). NMR. See Table 2.

Method b

5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole(3.45 g, 0.01 mol) was dissolved in 0.2M methanolic HBF₄ (100 ml) (2.5ml 50% HBF₄ and 97.5 ml CH₃ OH) and stirred at 37° C. for 2 min. Moremethanol (50 ml) was added and the mixture was stirred for another 3 minat 37° C. The mixture was cooled to 5° C., whereupon the desired mixtureof isomeric sulphenamide products (1A+1B) precipitated out. The productin the form of an isomeric mixture was filtered off and dried, yielding3.3 g (79%). NMR: See Table 2.

EXAMPLE 113-Methoxy-4,9,10-trimethyl-5H-pyrido[1',2':4,5][1,2,4]thiadiazino[2,3-a]benzimidazol-13-iumchloride (11)

(Method b)

5,6-Dimethyl-2-[[(4-methoxy-3-methyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole(1.60 g, 0.005 mol) was dissolved in 0.2M methanolic HCl (50 ml) (1 mlconc. HCl and 49 ml CH₃ OH) and stirred at 37° for 7 min. The solutionwas cooled and the desired sulphenamide salt precipitated. The productwas filtered off and dried, yielding 0.3 g (17%). NMR: See Table 2.

EXAMPLE 12Benzimidazo[1,2-b]pyrido[1,2,3-de][1,2,3]benzothiadiazin-14-ium,hexafluorophosphate (12)

(Method a)

2-[8-quinolinyl]-sulphinyl-1H-benzimidazole (1.50 g, 0.005 mol) wasdissolved in 0.2M methanolic HCl (50 ml) (1 ml conc. HCl and 49 ml CH₃OH) and the solution was stirred at 37° for 7 min. Conc. HPF₆ (1 ml) wasadded and the solution was cooled to 10° C. The desired sulphenamidesalt was filtered off as a crystalline material and dried. M.p. 199° C.

The starting compound was prepared according to the following method.

Preparation of 2-[8-quinolinyl]-thio-1H-benzimidazole

To 8-mercaptoquinoline hydrochloride (5.00 g, 0.025 mol) in ethanol (250ml) conc. HCl (2.25 ml) and 2-chlorobenzimidazole (3.86 g, 0.025 mol)were added. The mixture was refluxed overnight. pH was adjusted to 13.0by addition of 2M NaOH. Part of the solvent was evaporated off. Themixture was poured on ice-water. Filtration and recrystallization fromCH₃ CN gave the desired product (4.50 g, 65%), m.p. 215° C.

Preparation of 2-[8-quinolinyl]-sulphinyl-1H-benzimidazole

m-Chloroperbenzoic acid, 82% (3.42 g, 0.016 mol) dissolved in CH₂ Cl₂(100 ml) and cooled to -10° C. was added under stirring to2-[8-quinolinyl]-thio-1H-benzimidazole (4.50 g, 0.016 mol) dissolved inCH₂ Cl₂ (150 ml) maintaining the temperature at -5° C. Stirring wascontinued at -5° C. for 10 min. The CH₂ Cl₂ -solution was washed withNaHCO₃ (2.69 g, 0.032 mol) dissolved in water (100 ml). The organicphase was dried (Na₂ SO₄), filtered and the solvent was evaporated off.CH₃ CN was added to the residue and the mixture was warmed understirring. The precipitate was filtered off and washed with warm CH₃ CN,giving the desired product (2.40 g, 51%), m.p. 205° C.

    TABLE 1      Representative examples of compounds included in the scope of the     invention.      ##STR10##      IIIa            Identified by M.p. Example No. R.sup.1a R.sup.2a     R.sup.3a R.sup.4a R.sup.5a R.sup.6a R.sup.7a R.sup.8a X.sup.⊖     °C. or NMR         1A H OCH.sub.3 H H H CH.sub.3 OCH.sub.3 CH.sub.3 BF.sub.4 NMR   1B H     H OCH.sub.3 H H CH.sub.3 OCH.sub. 3 CH.sub.3 BF.sub.4 NMR   2A H     OCH.sub.3 H H H CH.sub.3 OCH.sub.3 CH.sub.3 PF.sub.6 NMR   2B H H     OCH.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3 PF.sub.6 NMR   3A H OCH.sub.3     H H H CH.sub.3 OCH.sub.3 CH.sub.3 AuCl.sub.4 NMR   3B H H OCH.sub.3 H H     CH.sub.3 OCH.sub.3 CH.sub.3 AuCl.sub.4 NMR  4 H H H H H CH.sub.3     OCH.sub.3 CH.sub.3 PF.sub.6 NMR  5 H H H H H CH.sub.3 OCH.sub.3 CH.sub.3     AuCl.sub.4 NMR  6 H H H H H H H H BF.sub.4 225   7A H CH.sub.3 H H     CH.sub.3 H H H BF.sub.4 NMR   7B H H CH.sub.3 H CH.sub.3 H H H BF.sub.4     NMR  8 H CH.sub.3 CH.sub.3 H CH.sub.3 H H H BF.sub.4 NMR  9 H CH.sub.3     CH.sub.3 H H H OCH.sub.3 H BF.sub.4 187 10 H CH.sub.3 CH.sub.3 H H     CH.sub.3 OCH.sub.3 H BF.sub.4 NMR 11 H CH.sub.3 CH.sub.3 H H CH.sub.3     OCH.sub.3 H Cl NMR 12 H H H H CHCHCH H H BF.sub.4 199 13 H CH.sub.3     CH.sub.3 H H CH.sub.3 H CH.sub.3 PF.sub.6 NMR 14 H H H H H CH.sub.3     CH.sub.3 H BF.sub.4 215 15 H H H H H CH.sub.3 CH.sub.3 H Cl 170 16     CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 H CH.sub.3 OCH.sub.2 CHCH.sub.2     CH.sub.3 Cl 17 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 H CH.sub.3 OCH.sub.3     CH.sub.3 PF.sub.6 18 H CH.sub.3 CH.sub.3 CH.sub.3 H CH.sub.3 OCH.sub.2   C     CHH.sub.2 CH.sub.3 BF.sub.4 19 H CH.sub.3 CH.sub.3 CH.sub.3 H CH.sub.3     OCH.sub.3 CH.sub.3 AuCl.sub.4 20 CH.sub.3 H CH.sub.3 CH.sub.3 H CH.sub.3 O     CH.sub.2 CHCH.sub.2 CH.sub.3 PF.sub.6 21 CH.sub.3 H CH.sub.3 CH.sub.3 H     CH.sub.3 OCH.sub.3 CH.sub.3 BF.sub.4 22 H H CH.sub.3 CH.sub.3 H CH.sub.3 O     CH.sub.2 CHCH.sub.2 CH.sub.3 AuCl.sub.4 23 H CH.sub.3 CH.sub.3 H H     CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 Cl 24 CH.sub.3 H H CH.sub.3 H     CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 Cl 25 H H H CH.sub.3 H CH.sub.3     OCH.sub.2 CHCH.sub.2 CH.sub.3 BF.sub.4 26 H H CH.sub.3 H H CH.sub.3      OCH.sub.2 CHCH.sub.2 CH.sub.3 AuCl.sub.4 27 H H OCH.sub.3 H H CH.sub.3     OCH.sub.2 CHCH.sub.2 CH.sub.3 PF.sub.6 28 H H OCH.sub.3 H H CH.sub.3     OCH.sub.2      CCH CH.sub.3 Cl 29 H H OCH.sub.3 H H CH.sub.3 O(CH.sub.2).sub.3     CHCH.sub.2 CH.sub.3 AuCl.sub.4 30 H H OCH.sub.3 H H CH.sub.3 O(CH.sub.2).     sub.3      CH.sub.3 CH.sub.3 Cl 31 H H OCH.sub.3 H H CH.sub.3 OCH(CH.sub.3).sub.2     CH.sub.3 PF.sub.6 32 H H OCH.sub.3 H H CH.sub.3 OC(CH.sub.3).sub.3     CH.sub.3 BF.sub.4 33 H H OCH.sub.3 H H CH.sub.3 OCH.sub.2 CH.sub.2     CH(CH.sub.3).sub.2 CH.sub.3 Cl 34 H CH.sub.3 OCH.sub.3 CH.sub.3 H H     CH(CH.sub.3).sub.2 CH.sub.3 PF.sub.6 35 H CH.sub. 3 H CH.sub.3 H     CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 BF.sub.4      36 H H     ##STR11##      H H CH.sub.3 OCH.sub.3 CH.sub.3 AuCl.sub.4      37 H H     ##STR12##      H H CH.sub.3 OCH.sub.3 CH.sub.3 PF.sub.6  38 H CH.sub.3 COOCH.sub.3 H H C     H.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 BF.sub.4 39 H H CH(CH.sub.3).sub.2     H H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 Cl 40 H H C(CH.sub.3).sub.3 H     H CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 AuCl.sub.4 41 H CH.sub.3     OCH.sub.3 CH.sub.3 H CH.sub.3 OCH.sub.3 CH.sub.3 BF.sub.4 42 H CH.sub.3     OCH.sub.3 CH.sub.3 H CH.sub.3 CH.sub.3 H AuCl.sub.4 43 H CH.sub.3     COCH.sub.3  CH.sub.3 H CH.sub.3 OCH.sub.3 CH.sub.3 PF.sub.6 44 H     CH.sub.3 COCH.sub.3 CH.sub.3 H CH.sub.3 H CH.sub.3 Cl 45 H CH.sub.3     COC.sub.2 H.sub.5 CH.sub.3 H CH.sub.3 OCH.sub.3 CH.sub.3 AuCl.sub.4 46 H C     H.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 OCH.sub.3 CH.sub.3 BF.sub.4     47 H CH.sub.3 CH.sub.3 CH.sub.3 H CH.sub.3 CH.sub.3 CH.sub.3 PF.sub.6 48     H CH.sub.3 C.sub.2 H.sub.5 CH.sub.3 H CH.sub.3 OCH.sub.3 CH.sub.3 Cl 49     H CH.sub.3 C.sub.2 H.sub.5 CH.sub.3 H CH.sub.3 OCH.sub.3 H PF.sub.6 50 H C     H.sub.3 CH(CH.sub.3).sub.2 CH.sub.3 H CH.sub.3 OCH.sub.3 CH.sub.3     BF.sub.4 51 H CH.sub.3 CH(CH.sub.3).sub.2 CH.sub.3 H CH.sub.3 CH.sub.3      CH.sub.3 AuCl.sub.4 52 H OCH.sub.3 Br OCH.sub.3 H CH.sub.3 OCH.sub.3     CH.sub.3 PF.sub.6 53 H OCH.sub.3 Br OCH.sub.3 H CH.sub.3 CH.sub.3 H     BF.sub.4 54 H C.sub.2 H.sub.5 CN C.sub.2 H.sub.5 H CH.sub.3 OCH.sub.3 H     AuCl.sub.4 55 H C.sub.2 H.sub.5 CN C.sub.2 H.sub.5 H CH.sub.3 OC.sub.2     H.sub.5 CH.sub.3 Cl 56 CH.sub.3 CH.sub.3 OCH.sub.3 CH.sub.3 H CH.sub.3     OCH.sub.3 CH.sub.3 Cl 57 CH.sub.3 H OCH.sub.3 CH.sub.3 H CH.sub.3     OCH.sub.3 CH.sub.3 BF.sub.4 58 CH.sub.3 H OCH.sub.3 CH.sub.3 H CH.sub.3     OCH.sub.3 CH.sub.3 AuCl.sub.4 59 OCH.sub.3 H OCH.sub.3 Cl H CH.sub.3     OCH.sub.3 CH.sub.3 PF.sub.6 60 H Cl Cl Cl H CH.sub. 3 OCH.sub.3 CH.sub.3     Cl 61 H CH.sub.3 CH.sub.3 H H H OCH.sub.3 C.sub.2 H.sub.5 AuCl.sub.4 62     H CH.sub.3 O(CH.sub.2).sub.6 CH.sub.3 CH.sub.3 H CH.sub.3 OCH.sub.3     CH.sub.3 Cl 63 H H C.sub.2 H.sub.5 H H CH.sub.3 OCH.sub.2 CHCH.sub.2     CH.sub.3 PF.sub.6 64 H H OCH.sub.3 H H CH.sub.3 O(CH.sub.2).sub.2     CH(CH.sub.3).sub.2 CH.sub.3 BF.sub.4 65 H H C(CH.sub.3).sub.3 H H     CH.sub.3 OCH.sub.2 CHCH.sub.2 CH.sub.3 Cl      66 H H     ##STR13##      H H CH.sub.3 OCH.sub.3 CH.sub.3 PF.sub.6  67 H H NO.sub.2 H H CH.sub.3     OCH.sub.3 CH.sub.3 BF.sub.4 68 H H Br H H CH.sub.3 OCH.sub.2 CHCH.sub.2     CH.sub.3 AuCl.sub.4      69 H CH.sub.3     ##STR14##      H H H OCH.sub.3 C.sub.2 H.sub.5 PF.sub.6  70 H CH.sub.3 CH.sub.3     CH.sub.3 H CH.sub.3 CH.sub.3 H BF.sub.4 71 H CH.sub.3 CH.sub.3 CH.sub.3     H H CH.sub.3 CH.sub.3 Cl 72 H CH.sub.3 CH.sub.3 CH.sub.3 H CH.sub.3 H     CH.sub.3 AuCl.sub.4 73 CH.sub.3 H CH.sub.3 CH.sub.3 H CH.sub.3 CH.sub.3     H BF.sub.4 74 H CH.sub.3 CN CH.sub.3 H CH.sub.3 OC.sub.2 H.sub.5     CH.sub.3 AuCl.sub.4 75 H H OCH.sub.3 H H H OCH.sub.3 C.sub.2 H.sub.5     PF.sub.6 76 H CH.sub.3 H CH.sub.3 H H OCH.sub.2 CHCH.sub.2 CH.sub.3 Cl     77 H H CF.sub.3 H H CH.sub.3 OCH.sub.3 CH.sub.3 AuCl.sub.4 78 H H     NO.sub.2 H H CH.sub.3 OCH.sub.3 CH.sub.3 BF.sub. 4 79 H H Cl H H     CH.sub.3 OCH.sub.3 CH.sub.3 PF.sub.6 80 H H H H H CH.sub.2 CH.sub.2     CH.sub.2 O H PF.sub.6  81 H OCH.sub.3 H H H CH.sub.2 CH.sub.2 CH.sub.2 O     H PF.sub.6 82 H H H H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 H Cl 83 H     OCH.sub.3 H H H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 H BF.sub.4 84 H H H     H H CH.sub.2 CH.sub.2 CH.sub.2 S H PF.sub.6 85 H OCH.sub.3 H H H H     CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 PF.sub.6  86 H OCF.sub.2 CHFO H H     CH.sub.3 OCH.sub.3 H PF.sub.6  87 H OCF.sub.3 CHFO H H H OCH.sub.3 H     PF.sub.6 88 H OCF.sub. 2 O H H CH.sub.3 OCH.sub.3 H Br 89 H OCF.sub.2 O     H H H OCH.sub.3 H Cl 90 H OCF.sub.2 O H H H OCH.sub.3 CH.sub.3 Cl 91 H     OCF.sub.2 CFClO H H CH.sub.3 OCH.sub.3 H BF.sub.4             92 H      ##STR15##      H H H CH.sub.3 OCH.sub.3 H Cl      93 H     ##STR16##      H H H H OCH.sub.3 H I      94 H     ##STR17##      H H H CH.sub.3 OCH.sub.3 H BF.sub.4  95 H OCF.sub.3 H H H CH.sub.3     OCH.sub.3 H PF.sub.6 96 H OCF.sub.3 H H H H OCH.sub.3 H Cl 97 H OCF.sub.3      H H H H OCH.sub.3 CH.sub.3 PF.sub.6 98 H OCF.sub.3 H H H CH.sub.3     OCH.sub.3 CH.sub.3 Cl 99 H OCF.sub.2 CHF.sub.2 H H H CH.sub.3 OCH.sub.3     H Br 100  H OCF.sub.2 CHF.sub.2 H H H H OCH.sub.3 H Cl 101  H OCF.sub.2     CHF.sub.2 H H H H OCH.sub.3 CH.sub.3 PF.sub.6 102  H OCH.sub.2 CF.sub.3     H H H CH.sub.3 OCH.sub.3 H PF.sub.6 103  H OCHF.sub.2 H H H CH.sub.3     OCH.sub.3 H PF.sub.6 104  H OCHF.sub.2 OCHF.sub.2 H H H OCH.sub.3 H     PF.sub.6 105       H OCHF.sub.2 OCH.sub.3 H H CH.sub.3 OCH.sub.3 H PF.sub.6

Identifying data for the compounds according to the examples 1-5, 7, 8,10, 11 and 13 are given in the following table 2.

                  TABLE 2                                                         ______________________________________                                        Compound                                                                      according to                                                                             NMR data (90 MHz)                                                  example    δppm (CD.sub.3 CN)                                           ______________________________________                                        1A        isomeric 2.53(s,3H), 2.63(s,3H), 3.97(s,3H), 4.37(s,3H),            1B        mixture  4.90(s,2H), 6.97-7.83(m,3H), 9.30(s,1H)                    2A        isomeric 2.53(s,3H), 2.63(s,3H), 3.93(s,3H), 4.37(s,3H),            2B        mixture  4.90(s,2H), 7.0-7.83(m,3H), 9.30(s,1H)                     3A        isomeric 2.50(s,3H), 2.60(s,3H), 3.90(s,3H), 4.30(s,3H),            3B        mixture  4.83(s,2H), 7.0-7.80(m,3H), 9.30(s,1H)                     4                  2.50(s,3H), 2.63(s,3H), 4.37(s,3H), 4.87(s,2H),                               7.30-7.60(m,3H), 7.6-8.0(m,1H), 9.37(s,1H)                 5                  2.47(s,3H), 2.60(s,3H), 4.33(s,3H), 4.87(s,2H),                               7.10-7.70(m,3H), 7.73-8.0(m,1H), 9.37(s,1H)                7A        isomeric 1.57(d,3H), 2.50 and 2.53 (2s, totally 3H),                7B        mixture  5.20(q,1H), 7.27-7.50(m,2H), 7.60-7.83(m,1H),                                 8.13-8.33(m,2H), 8.70-8.97(m,1H), 9.67(d,1H)               8                  1.60(d,3H), 2.47(s,3H), 2.50(s,3H), 5.23(q,1H),                               7.50(s,1H), 7.77(s,1H), 8.33(s,1H), 8.43(s,1H),                               8.90(d,1H), 9.80(d,1H)                                     10                 2.46(s,9H), 4.30(s,3H), 4.83(s,2H), 7.40-7.80                                 (m,3H), 9.50(d,1H)                                         11                 2.43(s,6H), 2.47(s,3H), 4.30(s,3H), 4.97(s,2H),                               7.20(s,2H), 7.40(d,1H), 9.50(d,1H)                         13                 2.43(s,3H), 2.50(s,3H), 2.63(s,3H), 2.70(s,3H),                               4.90(s,2H), 7.50(s,1H), 7.70(s,1H), 8.60(s,1H),                               9.47(s,1H)                                                 ______________________________________                                    

Incorporation of the new sulphenamides of the present invention inpharmaceutical preparations is exemplified by the following example.

EXAMPLE 80 Tablets

3-Methoxy-4,9,10-trimethyl-5-H-pyrido[1',2':4,5][1,2,4]thiadiazino[2,3-a]-benzimidazol-13-iumchloride (250 g), was mixed with

500 g lactose anhydrous

500 g microcrystalline cellulose

100 g crosslinked polyvinylpyrrolidone

in a mixer. 5 g of magnesium stearate was admixed and the mixture waspressed into tablets each weighing 275 mg.

BIOLOGICAL TESTS I. In Vitro Inhibition of Gastric H⁺,K⁺ -ATPase

Hog gastric H⁺,K⁺ -ATPase was purified according to Saccomani et al.,Biochim. Biophys, Acta 465, 311-330, 1977. 10 μg of membrane protein(GI-fraction in the reference listed above) was incubated with 2 mmol/lof piperazine-N,N'-bis-(2-ethane sulfonic acid) buffer pH 7,4 and thetest compound in concentrations 10⁻⁷ -10⁻⁴ M in a final volume of 1 ml.(The test compound was dissolved in methanol. Aliquots of these stocksolutions were diluted to a final methanol concentration below 1%, whichon its own had no effect on the enzyme activities.) After 30 minutes ofincubation, the remaining H⁺,K⁺ -ATPase activity was determined,according to Wallmark et al., Biochim. Biophys. Acta, 728, 31-38, 1983.A dose-response curve was constructed and the concentration athalf-maximal inhibition (IC₅₀) could be determined. When testing theisomeric mixture from Examples 1A and 1B and IC₅₀ =6.10⁻⁷ M wasobtained.

II. Inhibiting Effect in Vivo on Gastric Acid Secretion in Conscious Dog

Test Method

Chronic gastric fistula dogs were used. These dogs have been surgicallyprovided with a gastric cannula in the stomach and a duodenal fistulaused for direct intraduodenal administration of test compounds.Following a 4 weeks' recovery period after surgery, tests were performedonce a week on each dog. Food and water were withdrawn 18 hours beforeeach test.

The test compond was suspended in 0.5% Methocel® (90 HG, 15.000, DowChem Corp.), the pH was immediately adjusted to about 4 by addition ofhydrochloric acid and the suspension administered orally by using astomach tube. After 1 hour gastric acid secretion was induced bycontinuous infusion of histamine at individual doses (400-600 nmol/kg,h), resulting in approx. 90% of maximal secretion of gastric acid. Thegastric juice was collected by free flow from the gastric cannula inconsecutive 30 minutes samples for 2 hours. The samples were titrated topH 7.0 with 0.1M NaOH using a Radiometer automatic titrator and the acidoutput was calculated. The percent inhibition of acid secretion wascalculated by comparing in each dog the acid output in the tests to theacid output in control tests when only the vehicle was given. The peakinhibitory effect for each compound was determined. When testing theisomeric mixture from Examples 1A and 1B at a concentration of 4 μmol/kgan inhibition of 40% was obtained.

III. In Vivo Cytoprotective Effect: Effect on Ethanol-Induced GastricLesions in the Rat

Two groups of female Sprague-Dawley rats (190-220 g) were used, one forthe test compound and one for the control experiment. Food, but notwater, was removed 24 h before the experiments.

The animals in the test group were treated orally with the test compounddissolved in 0.01M HCl immediately before the test and the animals inthe control group were given the vehicle (0.01M HCl) in a dose of 1ml/kg.

Five or thirty minutes later the rats were given orally 1 ml of absoluteethanol (a standard agent for inducing gastric mucosal lesions).

Thirty minutes later the rats were killed by carbon dioxideasphyxiation, their stomachs dissected out and the gastric mucosae wereexamined for the presence of necrotic lesions. The total lengths of thelesions in the stomachs were measured in the test group and in thecontrol group, in both cases treated five and thirty minutes before withethanol.

When testing the isomeric mixture from Example 1A and 1B at a dose of 20μmol/kg the total lengths of lesions in the stomachs were reduced to 5.3cm (5 min) and 4.4 cm (30 min) compared to the lesions of the controls,which were 11.4 cm (5 min) and 10.4 cm (30 min). This indicates an ED₅₀-value below 20 μmol/kg.

The biological tests thus show that the compounds with the generalformula IIIa both inhibit gastric acid secretion and have agastrointestinal cytoprotecting effect.

We claim:
 1. A compound of the formula ##STR18## wherein R^(1a), R^(2a),R^(3a) and R^(4a) are the same or different and are selected from thegroup consisting ofhydrogen, alkyl of 1-7 carbon atoms, alkoxy of 1-7carbon atoms, fluorine or chlorine substituted alkoxy of 1-7 carbonatoms, halogen, --CN, --CF₃, --NO₂, --COR, --COOR, aryl of up to 10carbon atoms, and aryloxy of up to 10 carbon atoms, wherein R is alkylof 1 to 7 carbon atoms, cycloalkyl or 3 to 10 carbon atoms, aryl of upto 10 carbon atoms or aralkyl of up to 10 carbon atoms in the aryl groupand 1 to 7 carbon atoms in the alkyl group; R^(7a) is selected from thegroup consisting ofhydrogen, alkyl of 1-7 carbon atoms, alkoxy of 1-7carbon atoms, alkenyloxy of 2-5 carbon atoms, and alkynyloxy of 2-5carbon atoms; and R^(8a) is hydrogen or an alkyl group of 1-7 carbonatoms.